www.endoret.es

SKIN CARE

Endogenous Regenerative Technology

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BTI Biotechnology Institute is a Spanish biomedicine company focused on the development of translational research projects (R&D+i).

BTI is a world-level scientific leader in regenerative medicine using ENDORET in different fields of medicine.

MORE THAN 5000 M2 DEVOTED TO TRAINING, CLINICAL PRACTICE AND RESEARCH

Specific training aimed at different medical specialisations.

More than 40 scientific collaboration agreements with universities and research institutes all over the world.

More than 1200 students per year of all nationalities.

TRAINING

LEADER INREGENERATIVE MEDICINE

WE TRAIN IN ORDER TO OPTIMISE THE CLINICAL RESULTS

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20% of the workforce dedicated to research.

More than 15 years of research in tissue regeneration.

Prince Felipe Award for Technological Innovation.

Collaboration with experts from different countries in different fields of medicine for the development of clinically effective protocols.

RESEARCH

CLINICAL PRACTICE

TRANSLATIONAL RESEARCH: KNOWLEDGE ACQUIRED IN THE LABORATORY APPLIED TO CLINICAL PRACTICE

MORE THAN 100 INDEXED SCIENTIFIC PUBLICATIONS BACK THE EFFECTIVENESS AND BIOSAFETY OF ENDORET®

© BTI Biotechnology Institute

© BTI Biotechnology Institute

ENDORET® TECHNOLOGY SKIN CARE

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ENDORET® TECHNOLOGY

Hundreds of endogenous proteins affect the tissue repair processes, including angiogenesis, chemotaxis and cell proliferation. No exogenic agent can effectively govern all these processes. (1)

Endoret technology provides the necessary means for the isolation and concentration of the blood proteins involved in tissue regeneration, as well as its suitable application at the injury site. (2)

(1) Anitua E, Sánchez M, Orive G, Andia I. Delivering growth factors for therapeutics. Trends Pharmacol Sci. 2008;29:37-41.(2) Anitua E. Plasma rich in growth factors: preliminary results of use in the preparation of future sites for implants. Int J Oral Maxillofac Implants. 1999;14:529-535.(3) Anitua E, Sánchez M, Zalduendo MM, de la Fuente M, Prado R, Orive G, Andía I. Fibroblastic response to treatment with different preparations rich in growth factors. Cell Prolif. 2009;42:162-170.(4) Anitua E, Sánchez M, Nurden AT, Zalduendo M, de la Fuente M, Orive G, Azofra J, Andia I. Autologous fibrin matrices: a potential source of biological mediators that modulate tendon cell activities. J Biomed Mater Res A. 2006;77:285-293.(5) Anitua E, Zalduendo MM, Alkhraisat MH, Orive G. Release kinetics of platelet-derived and plasma-derived growth factors from autologous plasma rich in growth factors. Ann Anat. 2013.

© BTI Biotechnology Institute

ENDORET® IS A BIOMEDICAL TECHNOLOGY AIMED AT STIMULATING TISSUE REGENERATION BY APPLYING AUTOLOGOUS PROTEINS.

WHAT IS IT?1

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ACTIVE PRINCIPLE

ENDORET stimulates tissue regeneration due to its content in growth factors, in greater concentrations than those of blood. (3)

It is a temporary matrix that enables the balanced and gradual release of a large number of molecules, including growth factors and other proteins.(4) (5)

2

A. GROWTH FACTORS

B. FiBRin MeMBRAne

* p<0.05

pg/m

l

ng/m

l

PDGF* ng/ml *(PDGF ng/ml)

VEGF pg/ml

quANTIFICATION OF THE INCREASE IN VEGF (VASCulAR ENDOTHElIAl GROwTH FACTOR) AND PDGF (PlATElET DERIVED GROwTH FACTOR)

**

BASELINEENDORET

ENDORET® TECHNOLOGY SKIN CARE

© BTI Biotechnology Institute

200

150

100

50

0

200

150

100

50

0

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1. Promoting angiogenesis (6)

2. Stimulating cell migration (6)

3. Increasing cell proliferation (7)

4. Decreasing pain and inflammation (8)

5. Stimulating autocrine and paracrine secretion (8)

MECHANISMS OF ACTION3

SKIN CARE ENDORET® TECHNOLOGY

ENDORET TECHNOLOGY® REDUCES THE TISSUE REPAIR TIME(9) (10)

ENDORET ACCElERATES CEll MIGRATION FOR REGENERATIVE PuRPOSES (6)

SCAN THE CODE WITH YOUR SMARTPHONE TO WATCH THIS VIDEO

PROCESS ACCELERATED WITH ENDORET TECHNOLOGY®

NATURAL WOUND-HEALING PROCESS

RESPONSE OF THE TISSuE

RESPONSE OF THE TISSUE (Reduction in recovery time)

HAEMOSTASIS

INFLAMMATION

PROLIFERATION

REMODELLING

BASELINE (0H.) CONTROL (24H.) ENDORET® (24H.)

© BTI Biotechnology Institute © BTI Biotechnology Institute © BTI Biotechnology Institute

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With Endoret technology we can make 3 different therapeutic formulations and adapt them to the different clinical goals. (11)

Autologous product, there are no incompatibilities nor risk of rejection.

More than 700,000 patients have been treated in more than 20 countries, without any adverse effects being reported.

All the formulations of ENDORET have a bacteriostaticand bactericide effect, especially during the 4 hours after application.(12)(13)

2. CLOT 3. FIBRIN MEMBRANE

1. LIQUID

THERAPEUTIC FORMULATIONS4

SAFETY5

ENDORET® TECHNOLOGY SKIN CARE

(6) Anitua E, Troya M, Orive G. Plasma rich in growth factors promote gingival tissue regeneration by stimulating fibroblast proliferation and migration and by blocking transforming growth factor-ß1-induced myodifferentiation. J Periodontol. 2012 Aug;83(8):1028-37. (7) Anitua E, Prado R, Orive G. Bilateral sinus elevation evaluating plasma rich in growth factors technology: a report of five cases. Clin Implant Dent Relat Res. 2012;14:51-60.(8) Bendinelli P, Matteucci E, Dogliotti G, Corsi MM, Banfi G, Maroni P, Desiderio MA. Molecular basis of anti-inflammatory action of platelet-rich plasma on human chondrocytes: mechanisms of NF-kB inhibition via HGF. J Cell Physiol. 2012;225:757-766.(9) Sánchez M, Anitua E, Azofra J, Andía I, Padilla S, Mujika I. Comparison of surgically repaired Achilles tendon tears using platelet-rich fibrin matrices. Am J Sports Med. 2007;35:245-251.(10) Anitua E. Plasma rich in growth factors: preliminary results of use in the preparation of future sites for implants. Int J Oral Maxillofac Implants. 1999;14:529-535.(11) Anitua E, Sánchez M, Orive G, Andía I. The potential impact of the preparation rich in growth factors (PRGF) in different medical fields. Biomaterials. 2007;28:4551-4560.(12) Anitua E, Alonso R, Girbau C, Aguirre JJ, Muruzabal F, Orive G. Antibacterial effect of plasma rich in growth factors (PRGF) against Staphylococcus aureus and epidermidis strains. Clin Exp Dermatol. 2012.(13) Taschieri S, Del Fabbro M. Antimicrobial activity of pure platelet-rich plasma against microorganisms isolated from oral cavity. BMC Microbiol. 2013 Feb 25;13:47

© BTI Biotechnology Institute

© BTI Biotechnology Institute © BTI Biotechnology Institute

COSMETIC DERMATOLOGYThe infiltration of ENDORET promotes tissue remodelling in older skin affecting the hydration, angiogenesis and overall health of the skin. (14) (15)

In photoaged skin, endoret has a collagen remodelling effect and also reduces the solar elastosis.

DERMIS REMODELATION

(14) Anitua E, Sánchez M, Sarabia R, Sanz J, Aguirre JJ, Orive G. Eficacia y seguridad del PRGF (Plasma Rico en Factores de Crecimiento) en la regeneración cutánea facial. Effectiveness and safety of PRGF® (plasma rich in growth factors) in facial cutaneous regeneration. Clinical, randomised and controlled trial with hyaluronic acid. Revista de laAECEP.2011;Feb;23-33.(15) Dae Hun Kim, M.D. et al. Can Platelet-rich Plasma Be Used for Skin Rejuvenation? Evaluation of Effects of Platelet-rich Plasma on Human Dermal Fibroblast. Ann Dermatol Vol. 23, No. 4, 2011 (16) Anitua E, Sánchez M, Zalduendo MM, de la Fuente M, Prado R, Orive G, Andía I. Fibroblastic response to treatment with different preparations rich in growth factors. Cell Prolif. 2009 Apr;42(2):162-170.(17) Blanca Díaz Ley. Efectos del PRGF en el tratamiento del envejecimiento cutáneo. Comunicación oral de la XXV reunión GEDET. Alicante 29-30 Noviembre 2013.

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ENDORET increases the proliferation of the cells and improves the secretion of procollagen.(16,17)

IMPROVED SKIN CONSISTENCY

OF ENDORET TECHNOLOGY®APPLICATIONS

120,000*

40,000

20,000

60,000

80,000

100,000

No o

f cell

s

PROLIFERATIVE EFFECT ON THE FIBROBLASTS OF THE SKIN

Control Endoret

* p<0.05

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APLICACIONES ENDORET® SKIN CARE

An increase in hyaluronic acid is linked to better hydration of the skin.MORE HYDRATED SKIN

The skin is significantly more hydrated compared to treatment with hyaluronic acid, up to 3 and 6 months after treatment (14)

COMPARATIVE TEST WITH HYALURONIC ACID. % EVOluTION OF THE CORNEOMETRY COMPARED TO THE BASELINE FOR BOTH TREATMENT GROUPS* p<0.05

22

18

15

12

9

6

3

0

% va

riatio

n

*

*

3 months After 6 months

HYALURONIC ACID

ENDORET

11

3

22

15

MAINTAINED EFFECTS The activation of product enables the formation of a matrix in situ after the infiltration in the dermal area (18). Thus, the release of the Growth Factors is gradual prolonging the biological response. (19)

(18) Anitua E, Troya M, Orive G. Plasma rich in growth factors promote gingival tissue regeneration by stimulating fibroblast proliferation and migration and by blocking transforming growth factor-β1- induced myodifferentiation. J Periodontol. 2012 Aug;83(8):1028-1037.(19) Anitua E., Zalduendo M. et al; Release kinetics of platelet-derived and plasma-derived growth factors from autologous plasma rich in growth factors. Ann Anat. 2013.

ENDORET significantly increases the production of endogenous hyaluronic ACID. (16) (18)

HYALURONIC ACID PRODUCTION FROM SKIN FIBROBLASTS (16)

28

24

20

16

12

8

4

0

HA (μ

g/10

6 cell

s)

* p<0.05*

Control Endoret

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COMPONENTES ENDORET® SKIN CARE

WOUND HEALINGThe application technique of ENDORET on chronic skin ulcers significantly accelerates the healing process compared to conventional treatment. (20) (21) (22)

The autologous fibrin provides an excellent vehicle for the local release of growth factors, functioning as a matrix to support the new blood cells and helping the migration of cells to the injured area. (19)

(20) Molina-Miñano F, López-Jornet P, Camacho-Alonso F, Vicente-Ortega V. The use of plasma rich in growth factors on wound healing in the skin: experimental study in rabbits. Int Wound J. 2009 Apr;6(2):145-148.(21) Orcajo B, Muruzabal F, Isasmendi MC, Gutierrez N, Sánchez M, Orive G, Anitua E. The use of plasma rich in growth factors (PRGF-Endoret) in the treatment of a severe mal perforant ulcer in the foot of a person with diabetes. Diabetes Res Clin Pract. 2011 Aug;93(2):e65-67.(22) Anitua E, Aguirre JJ, Algorta J, Ayerdi E, Cabezas AI, Orive G, Andia I. Effectiveness of autologous preparation rich in growth factors for the treatment of chronic cutaneous ulcers. J Biomed Mater Res B Appl Biomater. 2008 Feb;84(2):415-421.

LONG-TERM VASCULAR ULCER

STATE OF THE WOUND AFTER ONE TREATMENT (1 WEEK AFTER)

WOUND CLOSURE IN 8 WEEKS.

TREATMENT OF AN ulCER wITH ENDORET.

The application of ENDORET to chronic skin ulcers significantly accelerates the healing process compared to conventional treatment.(22)

CONVENTIONAL TREATMENTENDORET TREATMENT

* p<0.05 ** p<0.01

*

* **

**

% OF AREA HEAlED

100

80

60

40

20

0

-20

-40

% a

rea

heale

d

weeks1 2 3 4 5 6 7 8

Treatment with ENDORET® on chronic ulcers achieved 73% healing after 8 weeks compared to 21% of the control group(21)

ACCELERATION OF HEALING

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SKIN CARE APLICACIONES ENDORET®

ENDORET achieves healing in 8 weeks for 45% of long-term ulcers (23)

55

50

45

40

35

30

25

20

15

10

5

0%

of w

ound

s hea

led

com

plet

elyTotal

ulcers ulcers more than

5 weeks old

ENDORETCONTROL

45,550

25

0

**

* p<0.05

The application of ENDORET accelerates the inflammatory process, decreases pain and increases the reepithelised area in wounds. (18) (20)

REDUCTION OF INFLAMMATION

All the formulations of ENDORET have a bacteriostatic and bactericidal effect. (13)

ANTISEPTIC EFFECT

(23) Aguirre JJ et al. Eficacia del PRGF-ENDORET en el tratamiento de las úlceras cutáneas secundarias a insuficiencia venosa: Ensayo clínico aleatorizado controlado con tratamiento convencional. Sent for publication.(24) López-Jornet P, Camacho-Alonso F, Molina-Miñano F, Vicente-Ortega V. Effects of plasma rich in growth factors on wound healing of the tongue. Experimental study on rabbits. Med Oral Patol Oral Cir Bucal. 2009 Sep 1;14(9):e425-428.(25) Anitua E, Orive G. Endogenous regenerative technology using plasma- and platelet-derived growth factors. J Control Release. 2012 Feb 10;157(3):317-320.(26) Platelets and wound healing. Front Biosci. 2008 May 1;13:3532-48.

OTHER TREATMENTSAll the formulations of ENDORET have a bacteriostatic and bactericidal effect.(24)(25)(26)

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OF ENDORET TECHNOLOGY®COMPONENTS

DISPOSABLE KITENDORET®

SINGLE-USE KIT*

COSMETIC KITS

WOUND HEALING KIT

1

* MEDICAl DEVICES CERTIFIED FOR APPlICATION IN DERMATOlOGY bY THE GERMAN NOTIFIED bODY TÜV

KMU 10Recommended for integral treatments.

· Get a total of 24 ml of product

KMU ESTHETICSGet 8ml for skin infiltration

· Plus 8ml to make a facial mask p· It includes infiltration material

KMU HEBTi innovation to get the endoret membranes quicker and easier, with all endoret regenerative properties.

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EQUIPMENT*

CERTIFICATION

ENDORET®

ENDORET®

2

4

THe AppliCATiOn OF endOReT TeCHnOlOGy COMplieS WiTH All THe ReGulATiOnS RequiRed By de SpAniSH AGenCy OF MediCineS And MediCAl deviCeS, FOOd And dRuG AdMiniSTRATiOn AGenCy (FDA) And euROpeAn uniOn. FOR euROpeAn uniOn OuR MediCAl deviCeS ARe idenTiFied WiTH CE MARk.

* MEDICAl DEVICES CERTIFIED FOR APPlICATION IN DERMATOlOGY bY THE GERMAN NOTIFIED bODY TÜV

· System IV Centrifuge· Work rack· Activation containers

We certify the clinical qualification and experience of our customers with our training certificates.

TRAININGENDORET®3

Exclusive training adapted to medical needs. We share our new clinical research and provide training for innovative, top-quality healthcare.

COMPONENTS OF ENDORET® SKIN CARE

© BTI Biotechnology Institute

Endoret is the most experienced technology of the market in the development of specific protocols for tissue regeneration, a pioneering technology manufactured exclusively by bTI biotechnology Institute.

© B

TI B

iote

chno

logy

Inst

itute

OPTIMUM CONCENTRATION OF PLATELETSThe right concentration of platelets affects the final efficacy. (26)

LEUKOCYTE - FREE FORMULATIONThe inclusion of leukocytes increases the pain and inflammation. (27)

CONTROLLED ACTIVATIONEnables the formation of the fibrin matrix in situ and the gradual release of growth factors, maintaining its efficacy over time. (28)

AUTOLOGOUSIt is made from the patient's own blood, so there are no known adverse effects. (29)

REPRODUCIBLEThe protocol for the preparation process and its clinical application is strictly defined and tested.

VERSATILEThree therapeutic formulations obtained in the same process means we can adapt the product to the patient's clinical needs. (30) (31)

OF ENDORET TECHNOLOGY®

ADVANTAGES

(26) Anitua E, Sanchez M, Prado R, Orive G. The type of platelet-rich plasma may influence the safety of the approach. Knee Surg Sports Traumatol Arthrosc. 2012.(27) Filardo G, Kon E, Pereira Ruiz MT, Vaccaro F, Guitaldi R, Di Martino A, Cenacchi A, Fornasari PM, Marcacci M. Platelet-rich plasma intra-articular injections for cartilage degeneration and osteoarthritis: single- versus double-spinning approach. Knee Surg Sports Traumatol Arthrosc. 2012.(28) Anitua E, Sanchez M, Nurden AT, Zalduendo M, de la Fuente M, Orive G, Azofra J, Andia I. Autologous fibrin matrices: a potential source of biological mediators that modulate tendon cell activities. J Biomed Mater Res A. 2006;77:285-293.(29) Anitua E, Sánchez M, Nurden AT, Nurden P, Orive G, Andía I. New insights into and novel applications for platelet-rich fibrin therapies. Trends Biotechnol. 2006;24:227-234.(30) Anitua E, Sánchez M, Orive G. Potential of endogenous regenerative technology for in situ regenerative medicine. Adv Drug Deliv Rev. 2010 Jun 15;62(7-8):741-52.(31) Anitua E, Sánchez M, Orive G, Andía I. The potential impact of the preparation rich in growth factors (PRGF) in different medical fields. Biomaterials. 2007 Nov;28(31):4551-60.

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ENDORET® TECHNOLOGY SKIN CARE

SAFETY AND REGULATORY ASSURANCE

The application of Endoret technology complies with all the regulations required by de Spanish Agency of Medicines and Medical devices, Food and drug Administration Agency (FdA) and european union.

QUALITY ASSURANCE

· The ENDORET closed-technique system complies with the highest standards of quality.

· Both the technology and the materials related to it have the CE health certificate awarded by TÜv for their specific application in: Soft tissue regeneration for treating skin ulcers and treatment of skin aging.

GUARANTEES OF EFFICACY

· BTI has the greatest clinical support in the world published in this field; its effectiveness is proven in more than 100 international scientific publications.

ADDITIONAL GUARANTEES

· BTI certifies its customers' specific training in the use of this technology.

· In addition, BTI guarantees the traceability of its materials, and helps transfer all necessary information to its patients.

BTI Biotechnology InstituteSan Antonio, 15 · 5º01005 Vitoria-Gasteiz (Álava) · SPAINTel: +34 945 140 024Fax: +34 945 135 203pedidos@bticomercial.com

USA1730 Walton RoadSuite 110Blue Bell, PA 19422-1802 · USATel: (12) 156 464 067Fax: (12) 156 464 066bti@bti-implant.us

UK 870 The CrescentColchester Business Park · ColchesterEssex CO49YQ · UNITED KINGDOMTel: (44) 01206580160Fax: (44) 01206580161info@bti-implant.co.uk

GERMANYMannheimer Str. 1775179 Pforzheim · GermanyTel: (49) 723 1428 060Fax: (49) 72314 280 615info@bti-implant.de

ITALYPiazzale Piola, 120131 Milan · ItalyTel: (39) 02 7060 5067Fax: (39) 02 7063 9876bti.italia@bti-implant.it

MEXICO Ejercito Nacional Mexicano, 351 · 3ACol. Granada Delegación Miguel HidalgoMéxico DF · CP 11520 · MexicoTel: (52) 55 52502964Fax: (52) 55 55319327bti.mexico@bti-implant.com

PORTUGALPraça Mouzinho de Albuquerque, 113 · 5º4100 359 Porto · PortugalTel: (+351) 22 120 1373Fax: (+351) 22 1201311bti.portugal@bticomercial.com

www.endoret.es

Cat. 075 ENG -Endoret

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ev.0 MAY 2014